Acetaminophen (Formula 1), chemically named N-acetyl-p-aminophenol, is one of the most widely used medications in the United States.

Acetaminophen is an over-the-counter analgesic and antipyretic, commonly sold under the trade name Tylenol®. Acetaminophen is classified as a mild analgesic. It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics such as codeine, oxycodone, and hydrocodone, acetaminophen can also be used in the management of more severe pain such as post-surgical pain and providing palliative care in advanced cancer patients.
When administered in proper therapeutic doses, acetaminophen is considered safe and harmless. Unfortunately, misuse and overdose of the drug can lead to hepatotoxicity and even, death.
Acetaminophen induced hepatotoxicity arises from impaired metabolism of acetaminophen monomers by the liver. Acetaminophen has a single phenolic hydroxyl group that confers photo instability and undergoes rapid pre-systemic metabolism (first-pass metabolism) in the liver, and to a lesser extent in the kidneys and intestine.
Acetaminophen (e.g., acetaminophen monomer) is metabolized via conjugation with sulfate or glucuronide to form sulfate esters or glucuronide esters. A small percentage of the drug (about 5%-10%) is oxidized by CYP450 enzymes (CYP2E1, 1A2, 2A6 and 3A4) to a hepatotoxic, reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI can be detoxified by rapid conjugation with glutathione, a sulfhydryl donor, and is eliminated in the urine or bile. However, if NAPQI is in excess or if glutathione stores are reduced, for example, by 70% compared to normal, NAPQI covalently binds to the cysteinyl sulfhydryl groups of proteins in the liver to form NAPQI-protein adducts. These NAPQI-protein adducts target mitochondrial proteins and ion channels of hepatocytes, leading to loss of energy production, ion misbalance, and cell death. As such, improper metabolism of acetaminophen can lead to hepatocellular damage, hepatic dysfunction, hepatic necrosis and organ failure.
Dosing recommendations have been established to minimize the risk of hepatotoxicity. According to current FDA guidelines for oral or rectal dosages of acetaminophen for treating pain, the maximum totally daily dose for adults is 3 g, with no more than 650 mg every 6 hours. For children under 12 years of age and/or less than 50 kg in weight, the maximum daily dose is 75 mg/kg, with a recommended dose of 10-15 mg/kg per dose every 4-6 hours but no more than 5 doses over a 24-hour period.
For intravenous dosing of adults and children equal or less than 50 kg in weight, the maximum total daily dose is 4 g, with no more than 1 g every 6 hours. For those less than 50 kg in weight, the maximum total daily dose is 75 mg/kg in 24 hours (up to 3750 mg), with no more than 15 mg/kg.
The minimum toxic dose of acetaminophen by oral administration is about 7.5 g to about 10 g for adults and about 150 mg/kg to about 200 mg/kg for children. Ingestion of more than 150 mg/kg or 12 g of acetaminophen by an adult is considered a toxic dose with a risk of developing hepatotoxicity. A comparable toxic dose for a child is more than 250-350 mg/kg.
Acetaminophen is not recommended for subjects who may develop hepatotoxicity upon receiving the drug. There is a need for an analgesic that has a lower likelihood of causing hepatotoxicity in a subject in need of pain relief.